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A Vigilant, Hypoxia-Regulated Heme Oxygenase-1 Gene Vector in the Heart Limits Cardiac Injury After Ischemia-Reperfusion In Vivo

Department of Physiology and Biophysics, College of Medicine, University of South Florida, St. Petersburg, FL

Keping Qian, PhD

Children’s Research Institute, Department of Pediatrics, College of Medicine, University of South Florida, St. Petersburg, FL

Y. Clare Zhang, Ph.D

Children’s Research Institute, Department of Pediatrics, College of Medicine, University of South Florida, St. Petersburg, FL

Leping Shen, MS

Children’s Research Institute, Department of Pediatrics, College of Medicine, University of South Florida, St. Petersburg, FL

M. Ian Phillips, PhD, DsC

Department of Physiology and Biophysics, College of Medicine, University of South Florida, St. Petersburg, FL

Objectives: The effect of a cardiac specific, hypoxia-regulated, human heme oxygenase-1 (hHO-1) vector to provide cardioprotection from ischemia-reperfusion injury was assessed. Background: When myocardial ischemia and reperfusion is asymptomatic, the damaging effects are cumulative and patients miss timely treatment. A gene therapy approach that expresses therapeutic genes only when ischemia is experienced is a desirable strategy. We have developed a cardiac-specific, hypoxia-regulated gene therapy "vigilant vector" system that amplifies cardioprotective gene expression.

Methods: Vigilant hHO-1 plasmids, LacZ plasmids, or saline (n = 40 per group) were injected into mouse heart 2 days in advance of ischemia-reperfusion injury. Animals were exposed to 60 minutes of ischemia followed by 24 hours of reperfusion. For that term (24 hours) effects, the protein levels of HO-1, inflammatory responses, apoptosis, and infarct size were determined. For long-term (3 week) effects, the left ventricular remodeling and recovery of cardiac function were assessed.

Results: Ischemia-reperfusion resulted in a timely overexpression of HO-1 protein. Infarct size at 24 hours after ischemia-reperfusion was significantly reduced in the HO-1-treated animals compared with the LacZ-treated group or saline-treated group (P < .001). The reduction of infarct size was accompanied by a decrease in lipid peroxidant activity, inflammatory cell infiltration, and proapoptotic protein level in ischemia-reperfusion-injured myocardium. The long-term study demonstrated that timely, hypoxia-induced HO-1 overexpression is beneficial in conserving cardiac function and attenuating left ventricle remodelling.

Conclusions: The vigilant HO-1 vector provides a protective therapy in the heart for reducing cellular damage during ischemia-reperfusion injury and preserving heart function.

Key Words: ischemia-reperfusion injury • vigilant heme oxygenase-1 vector • inflammatory response

Journal of Cardiovascular Pharmacology and Therapeutics, Vol. 10, No. 4, 251-263 (2005)
DOI: 10.1177/107424840501000405


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